J. Org. Chem. 2000, 65, 2773-2777
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Palladium-Catalyzed Cyclocarbonylation of o-Iodoanilines with Heterocumulenes: Regioselective Preparation of 4(3H)-Quinazolinone Derivatives Chitchamai Larksarp and Howard Alper* Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5 Received December 16, 1999
A catalyst system comprising palladium acetate-bidentate phosphine is effective for the cyclocarbonylation of o-iodoanilines with heterocumulenes at 70-100 °C for 12-24 h to give the corresponding 4(3H)-quinazolinone derivatives in good yields. Utilizing o-iodoaniline with isocyanates, carbodiimides, and ketenimines for the reaction, 2,4-(1H,3H)-quinazolinediones, 2-amino4(3H)-quinazolinones and 2-alkyl-4(3H)-quinazolinones were obtained, respectively. The nature of the substrates including the electrophilicity of the carbon center of the carbodiimide, and the stability of the ketenimine, influence the product yields of this reaction. Urea-type intermediates are believed to be generated first in situ from the reaction of o-iodoanilines with heterocumulenes, followed by palladium-catalyzed carbonylation and cyclization to yield the products. Introduction 4(3H)-Quinazolinone derivatives are of considerable interest because of their pharmacological properties;1 e.g., protein tyrosine kinase inhibitor,2 cholecystokinin inhibitor,3 antimicrobial,4 anticonvulsant,5 sedative and hypotensive,6 antidepressant and antiinflammatory,7 as well as antiallergy.8 In addition, more than 40 alkaloids comprised of a 4(3H)-quinazolinone moiety were isolated from natural sources.9 Some of these have interesting biological properties such as antimalarial activity and biofungicide10 and diuretic properties. There are a number of methods described for the preparation of the (1) (a) Armarego, W. L. F. Quinazolines; Brown, D. J., Ed.; John Wiley & Sons, Ltd: London, 1967. (b) Ellis, G. P. Synthesis of Fused Heterocycles; John Wiley & Sons Ltd.: Chichester, 1987; Vol. 47. (c) Hermecz, I.; Ko¨ko¨si, J.; Poda´nyi, B.; Sza´sz, G. Heterocycles 1994, 37, 903. (2) Wagner, G.; Wunderlich, I. Pharmazie 1978, 33, 15. (3) (a) Yu, M. J.; McCowan, J. R.; Mason, N. R.; Deeter, J. B.; G., M. L. J. Med. Chem. 1992, 35, 2534. (b) Padia, J. K.; Field, M.; Hinton, J.; Meecham, K.; Pablo, J.; Pinnock, R.; Roth, B. C.; Singh, L.; SumaChauhan, N.; Trivedi, B. K.; Webdale, L. J. Med. Chem. 1998, 41, 1042. (4) (a) Habib, O. M.; Moawad, E. B.; Girges, M. M.; El-Shafei, A. M. Boll. Chim. Farm. 1995, 134, 503. (b) Ibrahim, S. S.; Abdel-Halim, A. M.; Gabr, Y.; El-Edfawy, S.; Abdel-Rahman, R. J. Chem. Res., Synop. 1997, 154. (5) (a) Hori, M.; Iemura, R.; Hara, H.; Ozaki, A.; Sukamoto, T.; Ohtaka, H. Chem. Pharm. Bull. 1990, 38, 1286. (b) Wenzel, D. G. J. Am. Pharm. Assoc. 1955, 44, 550. (6) (a) Hayao, S.; Havera, H. J.; Strycker, W. G.; Leipzig, T. J.; Kulp, R. A.; Hartzler, H. E. J. Med. Chem. 1965, 8, 807. (b) Havera, H. J. J. Med. Chem. 1979, 22, 1548. (7) Lowe, J. A., III; Archer, R. L.; Chapin, D. S.; Cheng, J. B.; Helweg, D.; Johnson, J. L.; Koe, B. K.; Lebel, L. A.; Moore, P. F.; Nielsen, J. A.; Russo, L. L.; Shirley, J. T. J. Med. Chem. 1991, 34, 624. (8) LeMahieu, R. A.; Carson, M.; Nason, W. C.; Parrish, D. R.; Welton, A. F.; Baruth, H. W.; Yaremko, B. J. Med. Chem. 1983, 26, 420. (9) (a) Katritzky, A. R.; Rees, C. W. Comprehensive Heterocyclic Chemistry. The Structure, Reaction, synthesis and uses of Heterocyclic Compounds. Part 2B; Pergamon Press: New York, 1984; Vol. 3. (b) Pelletier, S. W. Alkaloids: Chemical and Biological Prospective; John Wiley & Sons Ltd.: New York, 1983; Vol. 1. (10) (a) Tsantrizos, Y. S.; Xu, X.-J. Can. J. Chem. 1993, 71, 1362. (b) Wang, H.; Genesan, A. J. Org. Chem. 1998, 63, 2432. (c) He, F.; Snider, B. B. J. Org. Chem. 1999, 64, 1397. (d) Sugimori, T.; Okawa, T.; Egushi, S.; Kakehi, A.; Yashima, E.; Okamoto, Y. Tetrahedron 1998, 54, 7997.
compounds. The main synthetic routes to such compounds utilize 2-aminobenzoic acid or its derivatives,11 2-aminobenzonitrile,12 isatoic anhydride,13 2-carbomethoxyphenyl isocyanate,14 N-arylnitrilium salts,15 and 4H-3,1benzoxazinones.16 Recently, the solid-phase synthesis of 2,4-(1H, 3H)-quinazolinediones have been reported.17 The direct ortho substitution of N-(tert-butoxycarbonyl)aniline by a lithium reagent was also described.18 Transition metals were utilized in the preparation of these compounds; e.g., Akazome et al.19 described the use of ruthenium and platinum complexes for the catalytic reduction N-heterocyclization of N-(2-nitrobenzoyl)amides under carbon monoxide pressure. A 2,4-(1H,3H)quinazolinedione was synthesized by the reaction of azobenzene with a stoichiometric amount of dicobalt octacarbonyl under CO pressure at 230 °C.20 The reaction of aromatic 2-carbamoylaniline with carbon monoxide (11) (a) Lalezari, I.; Stein, C. A. J. Heterocycl. Chem. 1984, 21, 5. (b) Kornet, M. J.; Varia, T.; Beaven, W. J. Heterocycl. Chem. 1984, 21, 1533. (c) Maillard, J.; Vincent, M.; Benard, M.; Jolly, R.; Morin, R.; Menillet, C. Chim. Ther. 1968, Mar-Apr, 100. (d) Papadopoulos, E. P.; Torres, C. D. J. Heterocycl. Chem. 1982, 19, 269. (e) Dean, W. D.; Papadopoulos, E. P. J. Heterocycl. Chem. 1982, 19, 1117. (f) Mayoral, J.; Melendez, E.; Mercha´n, F.; Sanchez, J. Synthesis 1981, 962. (g) Couture, A.; Cornet, H.; Grandclaudon, P. Synthesis 1991, 1009. (h) Paster, G.; Blanchard, C.; Montginoul, C.; Torreilles, E.; Giral, L. Bull. Soc. Chim. Fr. 1974, 1331. (i) Herlinger, H. Angew. Chem., Int. Ed. Engl. 1964, 3, 378. (j) Garin, J.; Melendez, E.; Mercha´n, F. L.; Tejero, T.; Villarroya, E. Synthesis 1963, 406. (12) (a) Taylor, E. C.; Shvo, Y. J. Org. Chem. 1968, 33, 1719. (b) Papadopoulos, E. P. J. Heterocycl. Chem. 1981, 18, 515. (c) Papadopoulos, E. P. J. Heterocycl. Chem. 1980, 17, 1553. (13) Minami, T.; Ogata, M.; Hirao, I. Synthesis 1982, 231. (14) Canonne, P.; Aksssira, M.; Dahdouh, A.; Kasmi, H.; Boumzebra, M. Heterocycles 1993, 36, 1305. (15) Al-Talib, M.; Jochims, J. C.; Hamed, A.; Wang, Q.; Ismail, A. E. Synthesis 1992, 697. (16) (a) Errede, L. A.; Oien, H. T.; Yarian, D. R. J. Org. Chem. 1977, 42, 12. (b) Doleschall, G.; Lempert, K. J. Monatsh. Chem. 1964, 95, 1068. (17) (a) Gouilleux, L.; Fehrentz, J.-A.; Winternitz, F.; Martinez, J. Tetrahedron Lett. 1996, 37, 7031. (b) Buckman, B. O.; Mohan, R. Tetrahedron Lett. 1996, 37, 4439. (18) Muchowski, J. M.; Venuti, M. C. J. Org. Chem. 1980, 45, 4798. (19) Akazome, M.; Kondo, T.; Watanabe, Y. J. Org. Chem. 1993, 58, 310. (20) Murahashi, S.; Horiie, S. J. Am. Chem. Soc. 1956, 78, 4816.
10.1021/jo991922r CCC: $19.00 © 2000 American Chemical Society Published on Web 04/04/2000
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and a stoichiometric or excess amount of selenium in the presence of N-methylpyrrolidine afforded 2,4-(1H,3H)quinazolinediones in fine yields.21 A combination of PdCl2(PPh3)2 and SnCl2 was reported for the intermolecular reductive N-heterocyclization of 2-nitrobenzamide to give the corresponding quinazolines.22 Palladium-catalyzed carbonylation reactions can serve as effective tools for the synthesis of heterocyclic-containing carbonyl moieties. The palladium-catalyzed carbonylation of aniline derivatives afforded 4H-3,1-benzoxazinones.23 We recently examined the utility of palladium catalysts for the preparation of benzo[e]-1,3-oxazin-4-one derivatives from o-iodophenols with heterocumulenes and carbon monoxide (eq 1).24
Larksarp and Alper Table 1. Determination of the Effect of Base on the Palladium-Catalyzed Cyclocarbonylation Reaction of 1a with 2aa
entry 1 2 3 4
Palladium-catalyzed carbonylation of a mixture of o-iodoanilines and lactams resulted in 3-52% yields.25 Encouraged by the usefulness of 4(3H)-quinazolinone derivatives, we decided to explore the preparation of the title compounds by palladium catalyzed cyclocarbonylation reactions of o-iodoanilines with heterocumulenes. We now wish to report a convenient method for the synthesis of 4(3H)-quinazolinone derivatives by treatment of o-iodoanilines with heterocumulenes such as isocyanates, carbodiimides, and ketenimines in the presence of a palladium catalyst under carbon monoxide pressure.
base (1.5 mmol) (iPr)
2NEt Et3N K2CO3 Na2CO3
isolated yieldb (%) 72 63 75 60
a Reaction conditions: 1a (1 mmol), 2a (2 mmol), base (1.5 mmol), Pd(OAc)2 (0.02 mmol), dppb (0.02 mmol), THF (5 mL), 300 psi CO, 80 °C, 12 h. b Isolated yield by silica gel column chromatography.
Using the Pd2(dba)3‚CHCl3-dppb catalytic system under the same reaction conditions in THF furnished 3a in 72% isolated yield. The effect of base used in the reaction was investigated in the reaction of 1a (1 mmol)
and 2a (2 mmol) in the presence of 0.02 mmol each of Pd(OAc)2 and dppb under 300 psi CO in THF, and the results are summarized in Table 1. Potassium carbonate (entry 2) gave results similar to those obtained by using diisopropylethylamine (entries 1 and 3), while slightly lower yields of 3a resulted from the reaction using triethylamine and sodium carbonate as the base (entries 2 and 4). Similar yields of 3a were observed in the reaction of 1a with 2a and K2CO3 under 300 psi CO, in the presence of 2 mol % Pd(OAc)2 in THF, using PCy3 (71%) compared to the same reaction employing dppb as the added ligand. Higher yields of 3a were obtained from the reaction employing PPh3 (85%) or 1,1′-bis(diphenylphosphino) ferrocene (dppf) (88%) as the ligand. It is worth noting that the use of dppb and dppf in some cases gave the same isolated product yield. Therefore, dppb and dppf were chosen to use as added ligands in this study. A variety of 3-substituted 2,4-(1H,3H)-quinazolinediones (3) can be prepared in moderate to good yields by the reaction of o-iodoanilines (1) with isocyanates (2) under carbon monoxide pressure in the presence of 2 mol % Pd(OAc)2-bidentate phosphine (dppb or dppf) catalyst and 1.5 mol % K2CO3 in THF at 70-80 °C for 12 h (see Table 2 for results). Two equivalents of isocyanates to o-iodoaniline was used since lower product yields may be obtained if 1 equiv is used.26 Isocyanates containing either electron-withdrawing or electron-donating groups on the aromatic ring react with o-iodoaniline to form 3-substituted 2,4-(1H,3H)-quinazolinediones (3) in good yields. o-Iodoaniline (1a), p-chloro-o-iodoaniline (1b), and p-methyl-o-iodoaniline (1c) were converted to 3 in this reaction. However, none of the desired product was isolated, using o-iodoaniline with a hydroxyl group
(21) Yoshida, T.; Kambe, N.; Murai, S.; Sonoda, N. Bull. Chem. Soc. Jpn. 1987, 60, 1793. (22) Akazome, M.; Yamamoto, J.; Kondo, T.; Watanabe, Y. J. Organomet. Chem. 1995, 494, 229. (23) (a) Larock, R. C.; Fellows, C. A. J. Org. Chem. 1980, 45, 363. (b) Cacchi, S.; Fabrizi, G.; Marinelli, F. Synlett 1996, 997. (c) Larksarp, C.; Alper, H. Organic Lett. 1999, 1, 1619. (24) Larksarp, C.; Alper, H. J. Org. Chem. 1999, 64, 9194.
(25) Mori, M.; Kobayashi, H.; Kimura, M.; Ban, Y. Heterocycles 1985, 23, 2803. (26) As reported in ref 24, using 2 mol equiv of isocyanate in the reaction with 1 mol of o-iodophenol gave better product yields than performing the reaction using a 1:1 ratio, possibly because dimerization or trimerization of the isocyanate may occur in the presence of base. See: (a) Hofmann, A. W. Ber 1860, 3, 761. Snape, H. L. J. Chem. Soc. 1886, 49, 254. (b) Hofmann, A. W. Ber 1885, 18, 764.
Results and Discussion Treatment of o-iodoaniline, 1a (1 mmol), and p-chlorophenylisocyanate, 2a (2 mmol),26 with 300 psi CO in benzene, in the presence of 0.02 mmol of Pd(OAc)2, 0.02 mmol of 1,4-bis(diphenylphosphino)butane (dppb), and (iPr)2NEt for 12 h at 80 °C afforded 3-(p-chlorophenyl)2,4-(1H,3H)-quinazolinedione (3a) in 44% isolated yield (eq 2). Performing the same reaction but using THF instead of benzene resulted in the isolation of 3a in 72% yield. Lower product yields were obtained when using DMF (56%) or DME (54%) as the solvent.
Pd-Catalyzed Cyclocarbonylation of o-Iodoanilines Table 2. Cyclocarbonylation Reactions of o-Iodoaniline (1) with Isocyanates (2) Catalyzed by Pd(OAc)2-Bidentate Phosphine Complexesa
entry 1 2 3 4 5 6 7 8 9 10 11
1 1a 1b 1c 1a 1a 1c 1d 1a 1c 1a 1c
R′NdCdO, 2, R′ ) p-ClC6H4, 2a 2a 2a p-BrC6H4, 2b p-CH3OC6H4, 2c 2c 2c C6H5, 2d 2d p-CH3C6H4, 2e 2e
J. Org. Chem., Vol. 65, No. 9, 2000 2775 Table 3. 2-Amino-(3H)-quinazolin-4-ones (5) from the Palladium-Catalyzed Reaction of o-Iodoanilines (1) with Carbodiimides (4) and Carbon Monoxidea
product
isolated yieldb (%)
entry
1
3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k
88d
1 2 3 4 5 6 7 8 9 10 11 12
1 1b 1c 1d 1a 1b 1d 1e 1a 1a 1a 1b
68d 72c 68d 80d 90c 0d 87d 89d 83c 77c
a Reaction conditions: 1/2/K CO /Pd(OAc) /bidentate phosphine 2 3 2 ligand, 1:2:1.5:0.02:0.02 mmol in 5 mL of THF, 70-80 °C, 300 psi CO, 12 h. b Isolated yield by silica gel column chromatography. c dppb was used in this reaction. d dppf was used in this reaction.
substituted at the C-4 of the phenyl ring (1d) in reaction with p-methoxyphenylisocyanate (2c) (entry 7). The latter may be due to competitive reactions of the hydroxyl and amine groups with the isocyanate, or to differences in the electrophilicity of the central carbon in isocyanates vs carbodiimides. 2-Amino-4(3H)-quinazolinones (5) can be prepared in moderate to good yields by utilizing the developed method with o-iodoaniline (1, 1 mmol), carbodiimide (4, 1 mmol), and 300 psi carbon monoxide, catalyzed by 2 mol % Pd(OAc)2 and dppf in the presence of 1.5 mmol K2CO3 in THF at 100 °C for 24 h (Table 3). Using o-iodoanilines with electron-withdrawing or electron-donating groups substituted on the phenyl ring does not have any effect on the selectivity of the reaction. The reaction tolerates nitrile as well as hydroxyl functional groups of o-iodoanilines (entries 4, 7, and 8). In contrast, using carbodiimides containing an electrondonating substituent on nitrogen, such as 4d-f, gave recovered starting material (entries 10-12). A possible mechanism for the palladium-catalyzed cyclocarbonylation reaction of o-iodoanilines (1) with isocyanates (2) or carbodiimides (4) is outlined in Scheme 1. Initial reaction of o-iodoaniline with an isocyanate or carbodiimide can give a urea (6a) or a guanidine (6b). Oxidative addition of the palladium catalyst to the C-I bond of 6a or 6b would afford 7. Carbonyl insertion into the latter and possible coordination of the NHR′′ moiety to the metal would afford the aroylpalladium intermediate 8. Reductive elimination would result in the formation of 3-substituted-4(3H)-quinazolinone derivatives. When carbodiimides are used as reactants, 4(3H)quinazolinone-2-imine intermediates 9 may be generated that, on rearrangement, would afford the more stable 2-amino-4(3H)-quinazolinones 5 (eq 3). Evidence for this process came from the reaction of N-methyl-o-iodoaniline
R′′NdCdNR′′, 4, R′′ ) product isolated yieldb (%) p-ClC6H4, 4a 4a 4a 4a C6H5, 4b 4b 4b 4b p-BrC6H4, 4c p-CH3C6H4, 4d C6H11, 4e iC3H7, 4f
5a 5b 5c 5d 5e 5f 5g 5h 5i
75 67 55 90 64 64 78 74 73 (61)c 0 0 0
a Reaction conditions: refer to the Experimental Section for the general procedure for the cyclocarbonylation of o-iodoanilines (1) with carbodiimides (4). b The products (5) were purified by silica gel column chromatography. c The yield in parentheses was obtained from the reaction using dppb as the ligand.
Scheme 1
(1f) with bis(p-chlorophenyl)carbodiimide (4a), which under the same reaction conditions afforded 1-methyl3-(p-chlorophenyl)-N-(p-chlorophenyl)-4(3H)-quinazolinone2-imine (9j) in 61% isolated yield (eq 4). Rearrangement did not occur here, since such a process would require a methyl rather than a hydrogen transfer. 2-Alkyl-4(3H)-quinazolinone derivatives can be synthesized by using ketenimines rather than carbodiimides in the reaction with o-iodoanilines and CO. Treatment of o-iodoaniline (1) with an equimolar amount of a ketenimine (10) at 300 psi CO, in the presence of 2 mol % each of Pd(OAc)2 and dppf, gave 2-alkyl-4(3H)quinazolinones (11) in good to excellent isolated yields (see Table 4 for results). Ketenimines 10a-c are quite
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Larksarp and Alper
Table 4. Palladium-Catalyzed Cyclocarbonylation Reactions of o-Iodoanilines (1) with Ketenimines (10)a
entry
1
10
product
Isolated yieldb (%)
1
1a
11a
98
2 3 4 5 6
1b 1c 1d 1e 1a
11b 11c 11d 11e 11f
87 99 45 47 72
7 8
1c 1a
11g 11h
74 95
9 10 11 12
1c 1a 1b 1b
11i 11j 11k
95 71 94 0
13
1b
PhNdCdC(CH3)(COOEt) 10a 10a 10a 10a 10a nBuNdCdC(CH )(COOEt) 3 10b 10b PhNdCdC(CH3)(COPh) 10c 10c PhNdCdC(COOEt)2 10d PhNdCdC(Ph)2 10e p-tolylNdCdC(Ph)2 10f
0
a Reaction conditions: refer to the Experimental Section for the general procedure for the cyclocarbonylation of o-iodoanilines (1) with ketenimines (10). b The products (11) were purified by silica gel column chromatography.
Scheme 2
tuted with aromatic groups, do not react with o-iodoanilines (entries 12 and 13). The palladium-catalyzed cyclocarbonylation reaction of ketenimines with o-iodoanilines may proceed in a pathway similar to that of isocyanates and carbodiimides. There are two conceivable amidine intermediates that can be formed in situ from the reaction of an o-iodoaniline with a ketenimine, namely 12 and 13. If 12 is formed, oxidative addition and carbonyl insertion followed by coordination of the amine unit to palladium, and subsequent reductive elimination would afford 14. Rearrangement of 14 would form the more stable 2-alkyl-4(3H)quinazolinone (11). An alternate pathway to 11 may involve oxidative addition and carbonyl insertion of 13 to give 15 Base-catalyzed intramolecular cyclization of 15 would form 11. In summary, the research reported herein constitutes simple methods for the synthesis of 2,4(1H,3H)-quinazolinediones, 2-amino-4(3H)-quinazolinones, and 2-alkyl4(3H)-quinazolinone derivative by palladium-catalyzed cyclocarbonylation reaction of o-iodoanilines with isocyanates, carbodiimides, and ketenimines, respectively.
Experimental Section
stable and can be used in the reaction to obtain high product yields. However, ketenimine 10d is not stable in air and should be kept under nitrogen at low temperature at all times. Therefore, freshly prepared 10d gave better product yields than a sample that was kept for more than 1 month. For example, 11k was obtained in 94% isolated yield (entry 11) when freshly prepared 10d was used and in 60% yield using 10d prepared 1 month earlier. Note that ketenimines, which are fully substi-
General Methods. Pd(OAc)2, phosphine ligands, o-iodoaniline (1a), dicyclohexylcarbodiimide (4e), diisopropylcarbodiimide (4f), and isocyanates (2) were purchased from commercial sources and were used as received. Carbodiimides (4a-d),27 p-chloro-o-iodoaniline (1b),28 p-methyl-o-iodoaniline (1c),28 p-hydroxy-o-iodoaniline (1d),29 p-cyano-o-iodoaniline (1e),30 N-methyl-o-iodoaniline (1f),31 ketenimines (10a-c,32 (27) Campbell, T. W.; Monagle, J. J.; Foldi, V. J. Am. Chem. Soc. 1962, 84, 3673. (28) Brewster, R. Q. In Organic Syntheses; Blatt, A. H., Ed.; John Wiley & Sons: New York, 1943; Collect. Vol. II, p 347. (29) Kvalnes, D. E. J. Am. Chem. Soc. 1934, 56, 667. (30) Chen, C.-Y.; Lieberman, D. R.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J.; Cottrell, I. F.; Houghton, P. G. Tetrahedron Lett. 1994, 35, 6981.
Pd-Catalyzed Cyclocarbonylation of o-Iodoanilines 10d,33 10e-f 34) and Pd2(dba)3‚CHCl335 were prepared according to literature procedures. Organic solvents were dried and distilled prior to use. General Procedure for the Palladium-Catalyzed Cyclocarbonylation of o-Iodoanilines (1) with Isocyanates (2a-e). An autoclave, its glass liner, and a magnetic stirring bar were dried in an oven and then cooled in a desiccator before use. The liner was charged with the palladium catalyst (2 mol %), 1 equiv of bidentate phosphine ligand, and 3 mL of dried solvent. After the mixture was stirred under nitrogen for 15 min, o-iodoaniline (1, 1 mmol), isocyanate (2, 2 mmol), 1.5 mmol of base, and another 2 mL of solvent were added to the mixture. The autoclave was then attached to a gauge block assembly and was flushed three times with CO and pressurized to 300 psi. After 12 h in an oil bath at 70-80 °C, the autoclave was removed and allowed to cool to room temperature. The excess gas was discharged and the system disassembled. The reaction mixture was then filtered, and the filtrate was concentrated and purified by column chromatography on silica gel using 1:1 mixture of ethyl acetate/pentane as the eluant. Melting points, IR, NMR, MS, and analytical data of selected 2,4-(1H,3H)-quinazolinediones 3 are as follows (see the Supporting Information for all other examples of 3). 3-(p-Chlorophenyl)-2,4-(1H,3H)-quinazolinedione (3a)11j (R ) H, R′′ ) p-ClC6H4): mp 296-297 °C (lit.11j mp 295-296 °C); IR 1725, 1649 cm-1; 1H (CDCl3 + DMSO-d6, 200 MHz) δ 6.59-7.10 (m, 7H), 7.45 (d, 1H, J ) 7.94 Hz), 10.99 (s, 1H, NH); 13C (CDCl3 + DMSO-d6, 75 MHz) δ 113.1, 114.5, 118.7, 121.6, 126.7, 127.4, 128.0, 129.2, 132.8, 134.0, 138.6, 149.3, 161.3; MS (m/e) 272 [M]+. 3-(p-Methoxyphenyl)-2,4-(1H,3H)-quinazolinedione (3e) (R ) H, R′′ ) p-CH3OC6H4): mp 293-295 °C (lit.11j mp 297299 °C); IR 1735, 1649 cm-1; 1H (CDCl3 + DMSO-d6, 200 MHz) δ 3.20 (s, 3H), 6.29 (m, 2H), 6.57-6.75 (m, 2H), 7.03-7.12 (m, 3H), 9.30 (s (br), 1H, NH); 13C (CDCl3 + DMSO-d6, 75 MHz) δ 54.1, 112.6, 120.5, 123.4, 127.1, 129.8, 135.3, 148.8, 149.8, 154.3, 158.3; MS (m/e) 268 [M]+. Anal. Calcd for C15H12N2O3: C, 67.16; H, 4.51; N, 10.44. Found: C, 67.02; H, 4.45; N, 10.45. General Procedure for the Palladium-Catalyzed Cyclocarbonylation of o-Iodoanilines (1) with Carbodiimides (4a-f) or with Ketenimines (10a-f). The cyclocarbonylation reactions of o-iodoanilines with carbodiimides or ketenimines were performed in the same manner as that for isocyanates except for the use of 1 equiv of a carbodiimide or ketenimine in THF. Two mol % of the Pd(OAc)2-ddpf catalyst system and K2CO3 were used for all reactions. The reaction (31) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63, 7652. (32) Frøyen, P. Acta Chem. Scand. 1974, B28, 586. (33) Bestman, H. J.; Lienert, J.; Mott, L. Liebigs Ann. Chem. 1968, 718, 24. (34) Stevens, C. L.; Singhal, G. H. J. Org. Chem. 1964, 29, 34. (35) Ukai, T.; Kawazura, H.; Ishii, Y. J. Organomet. Chem. 1974, 65, 253.
J. Org. Chem., Vol. 65, No. 9, 2000 2777 mixture was stirred in an oil bath at 100 °C for 24 h, cooled, and filtered. The filtrate was concentrated and then purified by silica gel column chromatography using a 1:1 mixture of ethyl acetate/pentane as the eluant. Melting points, IR, NMR, MS, and analytical data of selected examples of of 5 and 11 are as follows. (See the Supporting Information for all other examples of 5 and 11.) 2-(p-Chlorophenylamino)-3-(p-Chlorophenyl)-4(3H)quinazolinone (5a) (R ) H, R′′ ) p-ClC6H4): mp 175-177 °C; IR 1684, 1607 cm-1; 1H (CDCl3 200 MHz) δ 5.89 (s (br), 1H, NH), 7.22-7.66 (m, 11H), 8.15 (dd, 1H, J ) 7.90, and 1.50 Hz); 13C (CDCl3 75 MHz) δ 118.2, 122.2, 124.0, 125.6, 127.2, 128.9, 129.2, 130.5, 131.1, 132.7, 135.0, 136.2, 136.6, 145.7, 148.1, 162.2; MS (m/e) 380 [M - 2]+, 382 [M]+. Anal. Calcd for C20H13Cl2N3O: C, 62.84; H, 3.43; N, 10.99. Found: C, 63.00; H, 3.45; N, 10.98. 6-Methyl-2-(phenylamino)-3-phenyl-4(3H)-quinazolinone (5f) (R ) CH3, R′′ ) C6H5): mp 184-185 °C; IR 1686, 1606 cm-1; 1H (CDCl3 200 MHz) δ 5.98 (s (br), 1H, NH), 7.087.67 (m, 12H), 8.10 (d, 1H, J ) 2.38 Hz); 13C (CDCl3 75 MHz) δ 110.1, 121.0, 124.3, 126.4, 127.2, 128.9, 130.4, 130.9, 134.2, 135.0, 137.5, 146.5, 147.0, 161.4; MS (m/e) 346 [M - 1]+, 347 [M]+. Anal. Calcd for C20H14ClN3O; C, 69.07; H, 4.06; N, 12.08. Found: C, 68.75; H, 4.11; N, 12.02. 2-(1-Ethoxycarbonylethyl)-3-phenyl-4(3H)-quinazolinone (11a) (R ) H, R1) C6H5, R2 ) CH3, R3 ) COOEt): mp 75-76 °C; IR 1735, 1686 cm-1; 1H (CDCl3 200 MHz) δ 1.15 (m, 3H), 1.50 (m, 3H), 3.58 (m, 1H), 4.08 (m, 2H), 7.20-7.80 (m, 8H), 8.24 (m, 1H); 13C (CDCl3 75 MHz) δ 13.9, 15.7, 61.3, 120.9, 126.9, 126.9, 127.5, 128.2, 129.0, 129.4, 129.9, 134.4, 136.8, 147.3, 154.6, 162.3, 171.0; MS (m/e) 322 [M]+. Anal. Calcd for C19H18N2O3: C, 70.79; H, 5.63; N, 8.69. Found: C, 70.58; H, 5.68; N, 8.65. 2-(1-Ethoxycarbonylethyl)-3-n-butyl-4(3H)-quinazolinone (11g) (R ) H, R1 ) C4H9, R2 ) CH3, R3 ) COOEt): mp 54-55 °C; IR 1744, 1681 cm-1; 1H (CDCl3 200 MHz) δ 0.95 (t, 3H), 1.17 (t, 3H), 1.43 (m, 2H), 1.63 (m, 5H), 2.42 (s, 3H), 3.924.21 (m, 5H), 7.50 (m, 2H), 8.00 (s, 1H); 13C (CDCl3 75 MHz) δ 13.6, 14.0, 16.0, 20.1, 21.2, 31.1, 43.6, 44.1, 61.5, 120.3, 125.9, 127.1, 135.4, 136.7, 145.0, 153.8, 162.1, 170.9; MS (m/e) 316 [M]+. Anal. Calcd for C18H24N2O3: C, 68.33; H, 7.65; N, 8.85. Found: C, 68.47; H, 7.66; N, 8.97.
Acknowledgment. We are grateful to the NSERC of Canada for support of this research. C.L. is the recipient of a Chulabhorn Graduate Research Scholarship. Supporting Information Available: Spectral data of compounds 3a-f,h-k, 5a-i, and 11a-k; 1H and 13C NMR spectra of compounds 3b,d, 5g,i, and 11f. This material is available free of charge via the Internet at http:/pubs.acs.org. JO991922R
